CTSI Trainee Pilot supports better understanding of lupus

by Samreen Jatana
Special to the CTSI Stories Blog

Lupus is a devastating disease that affects around 1 in 2,000 people in the U.S., and involves chronic inflammation and tissue damage in various organs including the skin, kidneys, and joints. Although the mortality rate for lupus has improved in recent decades, a diagnosis of lupus often means elevated risk of early mortality and lifetime of immunosuppressive therapy, which can carry significant side effects.

AnnaBirdAnna Bird wants to improve treatment options. Bird, who is currently working towards a doctorate within the Immunology/Microbiology (IMV) graduate program in the laboratory of Jennifer Anolik, M.D., Ph.D., was recently awarded a CTSI Trainee Pilot Grant to study the immunologic mechanisms underlying the autoimmune disease, systemic lupus erythematosus (SLE).

Improving treatment options requires the development of more specific, targeted therapeutic approaches. But to make those improvements, researchers require a better understanding of the factors driving lupus pathogenesis, a project that Bird seeks to contribute to in her graduate research.

Specifically, she is using the CTSI Trainee Pilot as an opportunity to define the mechanisms underlying pathology observed in an under-characterized tissue in lupus: the bone marrow. Bone marrow in lupus often produces functionally abnormal or inadequate numbers of immune cells, and is a site where tissue necrosis and bone thinning are commonly observed. Evidence is accumulating that dysregulated cell production by the marrow contributes directly to lupus pathogenesis in peripheral tissues, as well as the high rate of infection that lupus patients experience.

Although it is poorly understood why lupus patients show marrow abnormalities, the work funded by the CTSI Trainee Pilot seeks to illuminate the mechanisms driving lupus pathogenesis within the bone marrow.

The CTSI project focuses on the neutrophil as a likely contributor to pathology in lupus marrow. Neutrophils contribute to inflammation in peripheral tissues including the vasculature and kidneys, and have been identified as a source of dying cell material and type I interferon, as well as B lymphocyte proliferation factors that are known to be central in driving B lymphocyte reactivity against self-tissues in lupus. Neutrophils develop abnormally in lupus and may be acquiring premature effector function that is responsible for elevated cell death seen in lupus marrow.

“Ultimately, this project will both assess whether neutrophils contribute to pathology in the marrow, as well as identifying the mediators responsible for abnormal neutrophil development in lupus,” said Bird. “This Pilot has provided a great opportunity for a translational investigation, incorporating a highly novel characterization of human bone marrow in lupus in combination with a murine model, which will allow me to tease apart the mechanisms underlying neutrophil defects in lupus.”

The CTSI Trainee Pilot has also provided a platform for collaboration between researchers in Hematology/Oncology, Immunology/Microbiology and the CTSI, as well as a foundation for generation of preliminary data that Anna can use to apply for the NIH K mechanism for future post-doctoral studies.

Success Stories: Trainee Pilot Program helps launch a career

The CTSI’s Trainee Pilot program offers aspiring researchers the chance to compete for a 1-year grant of up to $25,000. Courtney Jones, Ph.D., received one such award in 2012, and spoke with CTSI Stories about how the subsequent research helped shape her career.

Courtney Jones, Ph.D.

Courtney Jones, Ph.D.

Tell us a little about your research.

My dissertation centered on risk stratification of older adults with injuries. Certain hospitals, like Strong Memorial, are designated trauma centers that have specialized resources for the care of injured patients, and when we’re making a decision on where to send a patient, we want to make sure we choose the correct facility. We don’t want to send every injured patient to a designated trauma center, because then those centers may become overwhelmed. And we don’t want to send patients who are at high risk to a community hospital because they might not have the necessary resources to care for that person.

So when the ambulance arrives on the scene, it’s really about identifying where a patient should be transported. Previous research has shown that older adults are less likely to receive trauma center care than their younger counterparts, even if they have similar injuries. We really didn’t know why that was the case.

How did you come to work with the CTSI?

I was a Ph.D. student in epidemiology when I looked into the Trainee Pilot program, and it seemed really aligned with what I was doing because my research is very translational — it has the potential to really impact patient care. So the study that I proposed to the CTSI was to evaluate two hypothesized mechanisms that we thought were at play.

First, we knew there was this age based disparity in who receives trauma center care. There are national guidelines that EMS providers follow that outline things like systolic blood pressure, respiratory rate, and how the injury occurred — was it a high speed motor vehicle crash, or did they fall off a roof, for example — that determine where a patient should be transported.

The national guidelines are structured toward the most severely injured patients — the high-risk motor vehicle crashes, falls off a roof, the incidents that you might think about being on the 5:00 news. But in older adults, we know that even a simple fall can result in a pretty high risk of mortality and the need for substantial medical resources. So we’ve hypothesized that those guidelines just don’t work as well at identifying who is high risk.

We also evaluated this phenomenon where EMS providers might perceive older adults differently. There was some preliminary research done on the west coast that Identified potential reasons why older adults are more likely to be undertriaged – our goal was expand upon this previous research.

Very interesting. Can you describe your methods?

We created a quantitative survey that we administered to 600 EMS providers across the region, and we used a factorial survey method. We presented the EMS provider with a clinical scenario with different random patient characteristics. So one provider might get a vignette with a younger adult in a motor vehicle crash who had normal systolic blood pressure. And another EMS provider would have a different patient and scenario. And we’d ask: Would you take this patient to a trauma center? Then we analyzed the statistics and evaluated how they incorporated age into their decision.

The CTSI was great because it provided us the funds to do this complex, novel study in which we evaluated multiple components of decision-making, and it especially helped in recruiting the local providers to participate in the focus groups. We were able to provide food and beverages at each of the focus groups, and we provided incentives for participation, and I don’t think I would’ve had the same success — recruiting 600 EMS providers from a fairly small region — without the incentives and the support of the CTSI.

Any results you’d like to share?

What we found in the preexisting dataset is that the national guidelines don’t work as well among older adults. The sensitivity — or the ability of the national guidelines to correctly identify severely injured older adults — for individuals less than age 55 is about 80 percent, but for people over age 70, it’s only about 52 percent. And there’s a statistically significant linear decrease in sensitivity as age increases.

So that’s quite remarkable when you think about it. It has huge implications, because if the protocol they’re using in the field doesn’t work as well among older adults, then that might explain why we see that older adults are less likely to see trauma center resources.

The focus groups and factorial surveys we did with EMS providers also generated some interesting data. We failed to find a statistically significant difference in trauma center decision making between age groups, but the protocol states that age greater than 55 should be a special consideration. So if they were following the guidelines explicitly, they should’ve been more likely to transport the older patients to the trauma center. But, in fact, we failed to find such a difference.

The surveys also generated some interesting responses, such as the notion that injuries are just expected among older adults — that grandmas just fall out of bed sometimes – and as a result these injuries may not elicit the same response from providers. So that’s interesting because it speaks to what the next steps might be. Do we need to educate EMS providers? Do we need to structure the guidelines differently such that there are separate guidelines for older and younger adults?

How has your research progressed since then?

After completing the CTSI award, my primary mentor, Manish Shah, M.D. and I applied for an NIH R03 which evaluated a similar research question. We also got a CDC U01 grant that aligned perfectly with our previous research— it was an RFA for field triage decision-making for older adults taking anti-coagulants and platelet inhibitors. So in the U01 application we put a whole section of preliminary data that was essentially the findings and methodology I used in the CTSI award.

I also used the data as the basis for my future research which I outlined in NIH loan repayment award application, where they pay a portion of your student debt for you, and that was fantastic.

Overall, the CTSI was great because it was a catalyst — it was enough seed money to really show this was a worthy topic, and we got some really exciting findings which put me on a trajectory to really make this my career. We have presented the findings at numerous conferences and have manuscripts in-press and under-review.

Also, I was a Ph.D. student at the time so it was a really great opportunity for me to be a PI, if you will, before I became a faculty member. Because as a student, that’s an experience that often gets overlooked. You’re focused on your coursework and writing your dissertation, but grants management is never really part of your education. So just learning about the budgeting and the paperwork you have to fill out, that was something very complementary to my education and was a piece I wouldn’t have received otherwise.